We have been investigating the relationship between transfusional iron overload and immune function in patients with -thalassemia major. We have shown that B-cell activation exists in this disease concomitant with decreased NK function. Both the increase in B-cell activation and decrease in NK function are transfusion-related. We have also shown that the decreased NK activity can be reversed by iron-chelating agents in vitro. NK cells have recently been shown to regulate B-cell function in a wide range of animal and human experimental systems. We propose to investigate the interaction between NK cells and B-cells in thalassemia to determine first if a lack of regulation exists and if so whether it can be reversed by preincubation of NK-enriched fractions of thalassemia MNC with chelating agents. We also hope to distinguish between changes in immune function resulting from transfusion per se and iron overload by investigating immune function in patients who receive blood transfusions but do not have iron overload (kidney dialysis) and by investigating patients who have iron overload but receive few if any transfusions (thalassemia intermedia, idiopathic hemochromatosis). These studies should provide insight into the role of NK cells in regulating B-cell function and should provide evidence as to whether chelation therapy will result in an overall improvement or merely a readjustment of immunological defense mechanisms.